Haemophilia care in Arabic countries

compared to western European countries

(Yemen and Germany as examples)

Asllan Tahiraj

Aus der Klinik für Anästhesiologie der Ludwig-Maximillians-Universität München

Direktor: Prof. Dr. Bernard Zwissler

Abteilung für Transfusionsmedizin, Zelltherapeutika und Hämostaseologie

Leiter: Prof. Dr. Reinhard Henschler

Haemophilia care in Arabic countries

compared to western European countries

(Yemen and Germany as examples)

Dissertation zum Erwerb des Doktorgrades der Humanmedizin

an der Medizinischen Fakultät der

Ludwig-Maximillians-Universität zu München

Vorgelegt von

Asllan Tahiraj

aus Kukës, Albanien

2012

Mit Genehmigung der medizinischen Fakultät der Universität München

Berichterstater: Prof. Dr. med. h. c. Wolfgang Schramm

Mitberichtstatter: Prof. Dr. Angela Schuh

Dekan: Prof. Dr. med. Dr. h. c. Maximilian Reiser, FACR, FRCR

Tag der mündlischen Prüfung: 11.10.2012

Acknowledgments

It is a pleasure to thank those who made this thesis possible.

In the first place, I would like to thank Prof. Dr. med. H. c. Wolfgang Schramm for giving me the opportunity to work under his supervision in this field. His constant support and encouragement contributed significantly to the success of this work.

I am very thankful to Mrs. Dipl.-Kffr. Karin Berger for her interest in my work and her readiness to read, evaluate and improve this thesis.

I would like to show my gratitude to Dr. Assad Haffar from the World Federation of Haemophilia for his support and the very valued information about the Haemophilia care in Arabic countries. Special thanks and appreciations go for Dr. Ahmed Kaid and his team by Haematology Department at Thawra General Hospital in Sana’a, for their cooperation and kindness.

This thesis would not have been possible without the financial support from the Hanns-Seidel-Foundation. I consider that, this support is a valued contribution for improvement of Haemophilia care in Yemen. I also owe my deepest gratitude to the Honorary General Consul of Albania in Bayern, Mr. Franz Moedl for his stimulation, help and support to complete this work.

Last but not least, I offer my regards and blessings to my family, my parents and my wife, who supported me morally in any respect during the completion of the project.

“There is no disease that God has sent down except that He also has sent down its treatment.”

Prophet Muhammad

Table of contents

1 ABBREVATIONS ................................................................................................................................ 1

2 FIGURES AND TABLES ................................................................................................................... 2

3 SUMMARY ........................................................................................................................................... 4

4 INTRODUCTION ............................................................................................................................. 10

5 THEORETICAL PART ..................................................................................................................... 12

5.1 Haemophilia ...................................................................................................................................... 12

5.1.1 Definition ................................................................................................................................. 12

5.1.2 Genetics .................................................................................................................................... 12

5.1.3 Diagnosis ................................................................................................................................. 12

5.1.3.1 Clinical features ............................................................................................................... 12

5.1.3.2 Laboratory findings ......................................................................................................... 14

5.1.4 Medical treatment ................................................................................................................... 15

5.1.4.1 Clotting factor concentrates ........................................................................................... 15

5.1.4.2 Recombinant factor ......................................................................................................... 15

5.1.4.3 DDAVP ............................................................................................................................. 15

5.1.4.4 Gene therapy .................................................................................................................... 15

5.1.4.5 Comprehensive care concept ......................................................................................... 15

5.1.5 Prophylaxis .............................................................................................................................. 18

5.1.6 Complications ......................................................................................................................... 18

5.1.6.1 Inhibitor development ................................................................................................... 18

5.1.6.2 Infectious complications ................................................................................................. 19

5.1.6.2.1 Hepatitis ..................................................................................................................... 19

5.1.6.2.2 Human Immunodeficiency Virus .......................................................................... 19

5.1.6.2.3 Prions .......................................................................................................................... 19

5.1.6.3 Musculoskeletal complication ....................................................................................... 19

5.1.6.3.1 Muscle haematomas ................................................................................................. 20

5.1.6.3.2 Chronic haemophilic arthropathy .......................................................................... 20

5.1.6.3.3 Chronic synovitis ...................................................................................................... 20

5.1.6.3.4 Pseudotumor formation ........................................................................................... 21

5.1.6.3.5 Fractures...................................................................................................................... 21

5.2 Haemophilia in Arabic countries ................................................................................................. 22

5.2.1 Health care system in the Arabic region ............................................................................. 22

5.2.2 Haemophilia care in Arabic countries ................................................................................. 23

5.3 Haemophilia in Yemen .................................................................................................................... 25

5.3.1 Introduction to Yemen ........................................................................................................... 25

5.3.1.1 Geography and demography ......................................................................................... 25

5.3.1.2 Economy ........................................................................................................................... 27

5.3.1.3 Education .......................................................................................................................... 27

5.3.1.4 Health care system .......................................................................................................... 28

5.3.1.4.1 Public health care ...................................................................................................... 28

5.3.1.4.2 Private health care .................................................................................................... 31

5.3.1.4.3 Traditional ................................................................................................................. 32

5.3.1.4.4 Public-private interaction ........................................................................................ 32

5.3.1.4.5 Health insurance ....................................................................................................... 32

5.3.2 Epidemiology of Haemophilia in Yemen ............................................................................. 32

5.3.3 Haemophilia management .................................................................................................... 33

5.3.4 Costs and financial resources for haemophilic patients .................................................... 35

5.4 Haemophilia in Western European countries ............................................................................. 36

5.4.1 Health care in Western European countries ....................................................................... 36

5.4.2 Haemophilia care in the European region .......................................................................... 37

5.5 Haemophilia in Germany ............................................................................................................... 41

5.5.1 Introduction to Germany ........................................................................................................ 41

5.5.1.1 Geography and demography ......................................................................................... 41

5.5.1.2 Economy ........................................................................................................................... 41

5.5.1.3 Health care system .......................................................................................................... 42

5.5.2 Haemophilia care in Germany............................................................................................... 43

6 THE EMPIRICAL PART ................................................................................................................. 44

6.1 Study design ...................................................................................................................................... 44

6.2 Methods ............................................................................................................................................. 44

6.3 Patients ............................................................................................................................................... 44

6.4 Data sources and survey instruments ........................................................................................... 44

6.5 Data collection .................................................................................................................................. 44

6.6 Results ................................................................................................................................................ 45

6.6.1 Yemen ....................................................................................................................................... 45

6.6.1.1 Case collection .................................................................................................................. 45

6.6.1.2 Clinical manifestations .................................................................................................... 46

6.6.1.3 Concomitant diseases and complications .................................................................... 48

6.6.1.4 Treatment modality ......................................................................................................... 48

6.6.1.5 Cost of treatment ............................................................................................................. 49

6.6.2 Germany ................................................................................................................................. 50

6.6.2.1 Case collection .................................................................................................................. 50

6.6.2.2 Clinical manifestations .................................................................................................... 50

6.6.2.3 Concomitant diseases and complications .................................................................... 51

6.6.2.4 Treatment modality ......................................................................................................... 52

6.6.2.5 Cost of treatment ............................................................................................................. 53

6.7 Discussion .......................................................................................................................................... 54

6.8 Recommendations ............................................................................................................................ 57

7 REFERENCES ..................................................................................................................................... 58

8 APPENDIX .......................................................................................................................................... 64

1 Abbreviations

AAV Adeno Associated Virus AIDS Acquired Immunodeficiency Syndrome APTT Activated Partial Thromboplastin Time CJD Creuzfeldt Jacobs Disease CNS Central Nervous System CT Computed Tomography DDAVP 1-Desamino-8-D-Arginine Vasopressin DNA Deoxyribonucleic Acid EHC European Haemophilia Consortium ESCHQoL European Study in Clinical, Health Economic and Quality of Life EU European Union FFP Fresh Frozen Plasma GDP Gross Domestic Product GNI Gross National Income GIT Gastro-intestinal Tract HC-Av High Capacity Adenovirus HIV Human Immunodeficiency Virus HTC Haemophilia Treatment Centres ICB Intracranial Bleeding IU International Units MCH Mother and Child Health MRI Magnetic Resonance Imaging MOPH Ministry of Public Health NGO Non-governmental Organisation PHC Primary Health Care PT Prothrombin Time PWHA Person with Haemophilia A TCT Thrombin Clotting Time UAE United Arab Emirates VWD von Willebrand Disease VWF von Willebrand Factor WFH World Foundation of Haemophilia WHO World Health Organisation

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2 Figures and Tables

Figure index

Figure 1: Map of Yemen Republic……………………………………………………. 26 Figure 2: Composition of Yemeni population by age groups ...….……….………. 27 Figure 3: Life expectancy at birth among Yemeni population ……………………. 28 Figure 4: Map of Federal Republic of Germany………………………….................. 42 Figure 5: Educational level among Yemeni haemophiliacs ……………………….. 47 Figure 6: Age group distribution among Yemeni patients ………………………... 47 Figure 7: First bleeding site among Yemeni haemophiliacs......…………………… 48 Figure 8: Frequency of joint bleeding for Yemeni patients …….......……………… 48 Figure 9: Clinical presentation during last 6 months ………………………………. 49 Figure 10: Treatment modality in last 6 months ……………………………………... 49 Figure 11: Cost of treatment in last 6 months ………………………………………… 50 Figure 12: Frequency of joint bleeding among German patients …………………... 52 Figure 13 Clinical manifestations among German haemophiliacs ………………... 52 Figure 14: Complicated German cases ……………………………………………….. 53 Figure 15: Type of prophylaxis provided to German haemophiliacs....................... 53 Figure 16: Type of Factor concentrates used during last 6 months ……………….. 54

Table index

Table 1: Incidence of different sites of bleeding in percentages …………………… 14 Table 2: Incidence of bleeding in different joints …………………………………… 15 Table 3: Classification of severity of haemophilia ………………………………….. 15 Table 4: Health expenditure among Arabic countries ……………………………… 23 Table 5: Health status indicators in Arabic countries ………………………………. 24 Table 6: Some indicators of haemophilia care among some Arabic countries …... 25 Table 7: Demographic indicators on Yemen ………………………………………… 27 Table 8: Education indicators among Yemeni population ……………………….… 29 Table 9: Health expenditure indicators of Yemen ……………………………….….. 30 Table 10: Public Health facilities in Yemen ………………………………….………... 30 Table 11: Public Health Manpower ……………………………………….…………… 31 Table 12: Health facilities per 10000 of population ……………………………….…. 31 Table 13: Private Health facilities …………………………………………………….... 32 Table 14: Health expenditure among some western European countries …….…… 37

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Table 15: Some Health indicators among European countries……………….……... 38 Table 16: Central organization for haemophilia care ….………………………….…. 39 Table 17: Access to treatment for haemophilia patients in European countries ….. 40 Table 18: Indicators of haemophilia care in some western European

countries ………………………………………………………………….….… 41 Table 19: German Population and its gender distribution……………………….….. 42 Table 20: Live births and deaths among German population ………………….…… 43 Table 21: General characteristics of Yemeni patients …………………………….…... 46 Table 22: General characteristics of German haemophilic patients……………...….. 51

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3 Summary

A significant proportion of the world’s population is affected by hereditary defects in one or more of the clotting factors. Haemophilia A is a sex-linked genetic disorder resulting in deficiency of plasma factor VIII coagulant activity. Haemophilia B (Christmas disease) is due to deficiency of clotting factor IX [7, 8]. The clinical manifestations of haemophilia A and haemophilia B are indistinguishable, and occur in mild, moderate, and severe forms. The severe form of haemophilia is characterized mainly by frequent haemarthroses leading to chronic crippling haemarthropathy when not treated very early or prophylactically. Highly purified concentrates, prepared from human plasma or manufactured by recombinant technology, are available for treatment and are considered safe and effective [1, 2].

In developed countries, early treatment of bleeding episodes and home therapy quickly evolved as the primary management option. Presence of specialized interdisciplinary centres with 24 hours service, training and education of patients are the main advantages of the comprehensive treatment concept in developed countries. This is not the case in most developing countries where the government does not have the resources to buy the necessary quantities of coagulation factors in the face of more urgent health priorities and hardly any patients can afford to pay for their own treatment even for on-demand home therapy. Other problems are insufficient supply with clotting factor concentrates, lack of access to these concentrates and absence of specialized care centres [6].

Haemophilia care in Arabic region shows variations from country to country depending on socio economic status and varies from good organized care to absence of it at all. Only 13 of 21 Arabic countries have reported at least a Hemophilia Center and an organized care provided to haemophiliacs. Factor use per capita is low compared to western countries, and none of Arabic countries reached minimal level of 1 IU per capita. High income countries, such as Saudi Arabia, have reported a larger amount of factor concentrates, compared to those with lower income.

Haemophilia care in western European countries is a well organized process providing a qualified management to all haemophiliacs, through the Haemophilia treatment centers (HTCs) which exist in all the EU Member States. Choice and levels of treatment, availability of comprehensive care and access to prophylaxis vary widely from one Member State to another [31 ,72].

Yemen represents those Arabic countries where only a minimal care is provided to haemophilic patients. Facing other common and serious health problems, the health authorities pay only a small attention to haemophiliacs. In this country with a population of over 22 millions, and an estimated number of about 1460 haemophilia cases, there is no specialized center for treatment of haemophilia.

In Germany, people with haemophilia are entitled to a choice of all treatments ranging from an optimal level of factor replacement therapy on demand as well as on

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a prophylactic basis for those who need it, to comprehensive care at a Haemophilia Treatment Centre [81]. Haemophilia care in Germany is provided through 12 specialized Haemophilia Treatment Centers (HTC). Apart from treatment and care at the HTCs, specialized physicians in practices and at haematology units in general hospitals provide care. Home treatment is available for children as well as for adult people suffering from severe haemophilia[72].

In this short analysis, 20 Yemeni haemophilic patients were compared to 40 German patients. We analyzed demographic data, clinical manifestations, treatment options, complications and costs. The majority of Yemeni haemophiliacs, about 60 % of them, were children and the peak age was only 29 years. Alarming evidence is the fact that the Yemeni haematologists have not reported any patient older than 30 years.

In Yemen, despite the sufficient number of specialized haematologists, only two general hospitals located in the capital city provide some care to haemophilic patients. This care includes no prophylaxis program but only treatment on demand. It is offered only to severe affected cases and is based still on old medications such as Cryoprecipitate, FFP and DDAVP. About 65 % of the total cases participating in our study were treated with factor concentrates, which, even in cases with life threatening manifestations was not given in adequate amounts. During a period of 6 months, severe affected Yemeni haemophiliacs received an average of 1.157 IU of factor concentrates, or 90 times less than a German one. Access to factor concentrates was very difficult even for severe affected Yemeni haemophiliacs.

The awareness and education about the nature of disease among Yemeni haemophiliacs and their relatives is low, especially in rural areas, where most of Yemeni population lives. Couples who have haemophilic boys want to have still other children; circumcision, done routinely for all boys, is performed at home by a nurse, usually within the first 4 weeks of life, resulting in life threatening bleeding for haemophiliacs.

Absence of the health insurance system is another big challenge, as the patient should pay for every kind of health care and the costs of treatment are high compared to the income. The cost of care among Yemeni haemophilic patients during last 6 months varied from EUR 200 to EUR 2000, with an average of EUR 865 per patient. This amount of money exceeds the average of annual income among Yemeni population.

Under such conditions, without a health insurance, haemophilic patients face a big challenge on dealing with complications of the disease like transmitted infections or musculoskeletal complications. Facing those problems, the chances to survive are low and no haemophilic patient reaches the fourth decade of life. In a country as Yemen, where neither government nor the patient are able to pay for an adequate management of haemophilia,until now there is no initiative for creation of donators found in order to support people affected by this disease.

5

As a conclusion, we consider that the major problems facing haemophilia care in Yemen include: absence of a specialized center for treatment of haemophilia, inadequate supply with factor concentrates and lack of awareness and education about the nature of the disease.

We consider that the following recommendations will be useful for improvement of haemophilia care in Yemen:

• Initiation of a first step for a Haemophilia Center in Sana’a, as a result ofcoordination between Yemeni authorities and WFH representative for ArabicRegion

• Stimulation of a humanitarian financial support for Yemeni haemophiliacs,from rich Arabic neighbor countries (Saudi Arabia, Emirates, Qatar, Kuwait)

• Formulation of educational guidelines for haemophiliacs about the nature ofthe disease

• Organization of a national network and creation of a registry forhaemophiliacs

• Home therapy (living far away from capital city, Yemeni haemophiliacs haveto cross hundreds of miles to seek for some care)

• A twinning program between haemophilia centers in Germany and clinicsdealing with haemophilia in Yemen.

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Zusammenfassung

Erbliche Defekte in einem oder mehreren der Gerinnungsfaktoren gehören zu den seltenen Erkrankungen, sogenannten „Orphan diseases“. Hämophilie A ist eine geschlechtsgekoppelte genetische Erkrankung gekennzeichnet durch einen Mangel an Faktor VIII Gerinnungsaktivität. Bei Hämophilie B (Christmas disease) liegt der Defekt im Gerinnungsfaktor IX. Die klinische Symptome der Hämophilie A und Hämophilie B sind nicht unterscheidbar, und umfassen leichte, mittelschwere und schwere Formen. Die schwere Form der Hämophilie zeichnet sich durch häufige Gelenkblutungen aus, die zu schweren Gelenkdeformitäten und Verkrüppelung führen, wenn sie nicht rechtzeitig behandelt werden. Hochgereinigte Konzentrate, die aus humanem Plasma oder durch rekombinante Technologie hergestellt werden, sind für die Behandlung verfügbar und gelten als sicher und effektiv[1, 2].

In den entwickelten Ländern, ist eine Primärphrophylaxe mit Faktor VIII bei Kindern die Therapie der Wahl mit einer kontinuierlichen Faktor VIII Gabe durch „Home Therapy“, also Schulung der Eltern und Behandlung zu Hause. Organisation der Therapie in spezialisierten interdisziplinären Zentren mit 24-Stunden-Service, Schulung und Ausbildung von Patienten aller Altersgruppen, und sofortige Behandlung von Blutungen sind die wichtigsten Vorteile dieses umfassenden Behandlungskonzepts. Dies ist nicht der Fall in den meisten Entwicklungsländern, in denen die Regierung keine Finanzmittel bereitstellen kann, um die erforderlichen Mengen an Gerinnungsfaktoren zu kaufen. Die Patienten können es sich nicht leisten, die teure Faktor VIII-Behandlung zu bezahlen, auch nicht eine on-demand Therapie akuter Blutungen zu Hause. Grundsätzliche Probleme sind unzureichende Versorgung mit Gerinnungsfaktor-Konzentraten, fehlender Zugang zu ärztlicher Versorgung und das Fehlen spezialisierter Pflegeeinrichtungen[6].

Hämophilie Behandlung im arabischen Gebiet zeigt Variationen von Land zu Land je nach sozio-ökonomischem Status und variiert von gut organisierter Pflege bis völliger Abwesenheit einer Behandlungsmöglichkeit. Nur 13 von 21 arabischen Ländern haben überhaupt mindestens ein Hämophiliezentrum und eine organisierte Versorgung von Hämophilie-Patienten gemeldet. Faktor VIII Verbrauch pro Kopf ist im Vergleich zu westlichen Ländern gering, und kein einziges der arabischen Länder erreicht ein minimales Niveau von 1 IU Faktor VIII Verbrauch pro Kopf. Länder mit hohem Einkommen, wie Saudi-Arabien, haben einen größeren Verbrauch von Faktor VIII Konzentrat, im Vergleich zu arabischen Ländern mit niedrigerem Pro-Kopf-Einkommen ausgewiesen[31 ,72].

Jemen represäntiert die arabische Länder, in denen nur eine minimale Versorgung für hämophile Patienten erreichbar ist. Im Vergleich zu anderen überwiegenden , ernsthaften Erkrankungen, beachten die Gesundheitsbehörden hämophilie Patienten nur wenig. In diesem Land mit einer Bevölkerung von über 22 Millionen und einer geschätzten Anzahl von ca. 1460 Hämophilie Fällen, gibt es kein einziges spezialisiertes Zentrum für die Behandlung von Hämophilie-Patienten.

7

Hämophilie Behandlung in den westeuropäischen Ländern ist dagegen hervorragend organisiert und bietet qualifizierte Versorgung für alle Hämophilie-Patienten durch spezielle Hämophilie-Behandlungszentren an, die in allen EU-Mitgliedstaaten bestehen. Auswahl und Ebenen der Behandlung, die Verfügbarkeit einer umfassenden Versorgung, Faktor VIII Verbrauch und Zugang zu Prophylaxe variieren jedoch auch hier stark von einem Mitgliedstaat zum anderen .

In Deutschland können Patienten mit Hämophilie das Faktor VIII Konzentrat frei wählen, und erhalten eine umfassende Betreuung und Anleitung in 12 Hämophilie Behandlungs Zentren. Zusätzlich unterstützen spezialisierte Ärzte in Praxen und Krankenhäusern die Behandlung der Hämophilie Patienten. Prophylaxe ist für alle Kinder mit schwerer Hämophilie vorgesehen, sowie für erwachsene Patienten mit schwerer Hämophilie bei Bedarf[72].

In der vorliegenden Arbeit wurden 20 jemenitische Hämophilie Patienten mit 40 deutschen Hämophilie Patienten verglichen. Demographische Daten, klinische Erscheinungsformen, Behandlungsmöglichkeiten, Komplikationen und Kosten wurden in beiden Patientengruppen analysiert. Etwa 60% der jemenitischen Hämophilie Patienten waren Kinder. Der älteste Hämophilie Patient in dieser Gruppe was 29 Jahre alt. Laut Bericht jemenitischer Hämatologen wurde in der Abteilung kein Hämophilie Patient mit einem Alter über 30 Jahren gesehen.

Im Jemen bieten trotz einer ausreichenden Anzahl von spezialisierten Hämatologen nur zwei allgemeine Krankenhäuser in der Hauptstadt eine Minimalversorgung für Hämophilie Patienten an. Diese Versorgung umfasst kein Prophylaxe-Programm für Kinder mit Faktor VIII, sondern nur die Behandlung akuter Blutungen in schweren Fällen überwiegend mit veralteten Präparaten wie Kryopräzipitat, FFP und DDAVP. In über 65% der Gesamtzahl der Fälle, die in unserer Studie teilgenommen haben, wurden Faktor-Konzentrate gegeben, allerdings auch in Fällen mit lebensbedrohlichen Manifestationen nicht in ausreichender Menge. Während eines Beobachtungszeitraums von sechs Monaten erhielten die jemenitischen Patienten mit schwerer Hämophilie durchschnittlich 1.157 IE Faktor-Konzentrat (pro Patient), das heißt 90-mal weniger als ein deutscher Patient mit schwerer Hämophilie. Der Zugang zu Faktor VIII Konzentrat war auch für jemenitische Patienten mit schwerer Hämophilie und lebensbedrohlichen Blutungen sehr schwierig.

Die Sensibilisierung und Aufklärung über das Wesen der Krankheit unter jemenitischen Hämophilie Patienten und ihren Angehörigen ist niedrig, vor allem in ländlichen Gebieten, in denen der größte Teil der jemenitischen Bevölkerung lebt. Ehepaare mit hämophilen Jungen wollen noch andere Kinder haben. Die Beschneidung, die routinemäßig bei allen Jungen erfolgt, wird meistens zu Hause von einer Krankenschwester durchgeführt. Dies geschieht in der Regel innerhalb der ersten vier Lebenswochen und kann zu einer lebensbedrohlichen Blutung führen. Das Fehlen jeglicher Krankenversicherung ist eine weitere große Herausforderung, da der Patient für jede Art von Gesundheitsversorgung die Kosten der Behandlung selbst übernehmen muss. Die Kosten für die Behandlung bei jemenitischen Hämophilie Patienten im Beobachtungszeitraum von sechs Monaten variierte von

8

EUR 200 bis EUR 2000, mit durchschnittlichen Kosten von EUR 865 pro Patient. Dieser Betrag übersteigt das durchschnittliche Jahreseinkommen der jemenitischen Bevölkerung.

Die Überlebenschancen jemenitischer Hämophilie Patienten sind gering und kein Hämophilier erreicht das vierte Lebensjahrzehnt. In einem Land wie Jemen, wo weder Regierung noch der Patient in der Lage sind für eine angemessene Behandlung der Hämophilie zu zahlen, gibt es bis jetzt keine Initiative zur Bereitstellung von Spendengeldern um Menschen, die von dieser Krankheit betroffen sind, zu helfen.

Die großen Probleme der Hämophilie Versorgung im Jemen lassen sich wie folgt zusammenfassen: unzureichende Versorgung mit und Zugang zu Faktor Konzentraten, Abwesenheit von spezialisierten Zentren für die Behandlung von Hämophilie Patienten und unzureichende Aufklärung über die Art der Krankheit in der Bevölkerung, insbesondere in Zusammenhang mit der frühzeitigen Beschneidung der männllichen Kinder.

Folgende Empfehlungen zur Verbesserung der Hämophilie Behandlung in Jemen lassen sich daraus ableiten:

• Gündung eines Hämophilie-Zentrums in der Hauptstadt Sana'a, durch eineKooperation der jemenitischen Behörden mit WHF Vertretern für die arabische Region

• Beginn einer humanitären finanziellen Unterstützung für jemenitische HämophiliePatienten, mit Hilfe reicher arabischer Nachbarländer (Saudi-Arabien, Emirate, Qatar, Kuwait)

• Aufklärung von Hämophilie Patienten und ihrer Familien über die Art derKrankheit und ihre Folgen

• Organisation eines nationalen Netzes und die Schaffung eines Registers fürHämophilie Patienten

• Home-Therapie (weit weg von der Hauptstadt, müssen jemenitische HämophiliePatienten Hunderte von Meilen durchqueren, um eine Behaldlung zu bekommen)

• Gründung eines Twinning-Programms zwischen Hämophilie-Zentren inDeutschland und hämatologischen Kliniken in Jemen.

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4 Introduction

A significant proportion of the world’s population is affected by hereditary defects in one or more of the clotting factors. These defects lead to abnormal and sometimes life-threatening bleeding episodes.

Haemophilia is a group of X-linked bleeding disorders due to deficiency of clotting factors VIII (Haemophilia A) and IX (Haemophilia B). The clinical manifestations of haemophilia A and haemophilia B are indistinguishable, and occur in mild, moderate, and severe forms. They are the only blood clotting disorders inherited in a sex-linked pattern. The severe forms of haemophilia are characterized mainly by frequent haemarthroses leading to chronic crippling haemarthropathy when not treated very early or prophylactically. Highly purified concentrates, prepared from human plasma and manufactured by recombinant technology, are available for treatment and are considered to be safe and effective. The main complication of treatment is the development of antibody inhibitors against either factor VIII or factor IX, which are more common in patients with haemophilia A than in patients with haemophilia B[1, 2].

Haemophilia is the most severe bleeding disorder, after von Willebrand's disease which is the most common congenital bleeding disorder overall. In 2009, the World Federation of Haemophilia (WFH) has identified 153,251 people with haemophilia throughout the world[3]. This estimation included 91 % of world population.

The WFH estimates that the majority of people with haemophilia in the world do not receive adequate care. Seventy-five per cent of the global haemophiliacs lives in developing countries, where probably only one in five cases is diagnosed, and there is little or no care available[4].

Prior to the 1960s, when no adequate treatment was available, individuals with haemophilia suffered a similar fate worldwide. Severe joint disabilities appeared in early teens, and most patients died before the age of 20. At this time Haemophilia was treated primarily with fresh blood transfusions. Discovery of cryoprecipitate and subsequent development of clotting factor concentrates dramatically increased clinical management options. As concentrates could be easily stored, administered at home and carried with patients during travel, patients began to adopt a practice of home therapy[5].

Haemophilia as a disease and its management has a large impact on the community, including social integration and economics. Inability to be an active part of society and high cost of the medical care make this disease an important problem for all haemophilic patients.

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In developed countries, early treatment of bleeding episodes and home therapy quickly evolved as the primary management option. Presence of specialized interdisciplinary centres, training and education of patients are the main advantages of the comprehensive treatment concept in developed countries.

This is not the case in most developing countries where the government does not have the resources to buy the necessary quantities of coagulation factors in the face of more urgent health priorities and hardly any patients can afford to pay for their own treatment even for on-demand home therapy. Other problems are insufficient supply with clotting factor concentrates, lack of access to these concentrates and absence of specialized care centres [6].

In this short analysis we have taken two examples from two different parts of the world, Yemen and Germany. There is a big gap between these two countries regarding education, socio-economic status, health care and also haemophilia care, and we can assume that these two countries represent two extremities regarding health services provided to the community.

Taking in consideration that Germany has an advanced health care system with many facilities, potential human and financial resources, we want to find out the recent ways and strategies used for management of Haemophilia. On the other hand we have chosen Yemen, for two reasons: first, it is one of the developing countries facing many challenges in different fields of life, among which is the health care; and second, I studied there having the chance to know and touch the reality of this country. This Arabic country, rich in natural resources such as oil and gas, is suffering since many years from political crisis and instability, leading civil wars, poverty, absence of proper health care and education.

The primary objective of this study is to define useful recommendations and advices for clinics and hospitals that concern with this disease in Yemen. For that reason we will describe the management of haemophilia in Yemen and identify the major challenges and problems regarding the haemophilia care in this country. After that, will be described the management of haemophilia in western European countries, particularly in Germany.

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5 Theoretical part

5.1 Haemophilia

5.1.1 Definition Haemophilia A is a sex-linked genetic disorder resulting in deficiency of plasma factor VIII coagulant activity. Haemophilia B (Christmas disease) is due to deficiency of clotting factor IX[7, 8].

5.1.2 Epidemiology The incidence of haemophilia A is 1 in 10,000 live births, or 1 in 5,000 male births. Haemophilia B is less common with an incidence of 1 in 30,000 live male births. The prevalence rates are 105 and 28 per million male population for Haemophilia A and Haemophilia B respectively[4]. In 2009, 153,251 people with haemophilia throughout the world have been documented in a survey which included 105 countries and about 91 % of world’s population. About 43% of total documented haemophiliacs severe affected cases [3, 9].

5.1.3 Genetics The factor VIII and factor IX genes are located on the X chromosome. Many different defects in the gene have been identified, ranging from single-base changes to deletions and inversions. Major disruption of the gene, e.g. a large deletion, results in severe haemophilia whereas a single base change will only cause a partial loss of function, with moderate or mild disease [10]. As the factors’ gene is on the X chromosome, haemophilia is a sex-linked disorder. Thus all daughters of haemophiliacs are obligate carriers and sisters have a 50% chance of being a carrier. If a carrier has a son, he has a 50% chance of having haemophilia, and a daughter has a 50% chance of being a carrier. Carriers generally have adequate levels (> 60%) of clotting FVIII or FIX to control bleeding. However, clotting factor levels vary from one carrier to another due to lyonization, in which the expression of one of the two X chromosomes is randomly suppressed [11, 12]. A reduced factor VIII or IX level in a carrier will result in a mild bleeding disorder; thus all known or suspected carriers of haemophilia should have their factor VIII or factor IX level measured[10, 12].

5.1.4 Diagnosis

5.1.4.1 Clinical features Haemophilia results in prolonged oozing after injuries, tooth extractions, or surgery, and delayed or recurrent bleeding prior to complete wound healing. The age of diagnosis and frequency of bleeding episodes are related to the factor VIII clotting activity[7, 8]. It occurs in mild, moderate, and severe forms. Although patients with mild haemophilia usually bleed only after trauma or surgery, those with severe haemophilia A or B bleed spontaneously or after trivial trauma, particularly into joints and muscles[13].Soft tissue haematomas and haemarthroses leading to severe, crippling haemarthropathy are characteristic of the disease[14]. Subacute haemarthroses is generally associated with previous synovitis or arthropathy, while

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acute haemarthroses commonly occurs in a previously healthy joint. Acute bleeding is usually felt by the patient as a burning sensation in the joint. Haemarthroses develops within a few hours; the joint becomes inflamed, tense, warm, and the skin becomes bright red. The affected joint is held in an antalgic flexion position, with painful and limited mobility[15, 16].

Muscle haematomas are also characteristic of haemophilia. These occur most commonly in the calf and psoas muscles but they can arise in almost any muscle. The untreated child almost always has subcutaneous hematomas; some have been referred for evaluation of possible non-accidental trauma[7, 8].

Haematuria is less common than joint or muscle bleeding in individuals with haemophilia, but the most severely affected patients, have one or two episodes per decade. These may be painless and resolve spontaneously, but, if bleeding is heavy, it can produce clot colic. Clots may obstruct renal tubules or the ureter, causing temporary hydronephrosis[16].

Possibly the most frequently encountered emergent haemorrhagic event in haemophilia management is central nervous system (CNS) bleeding. Most of these events, which involve bleeding inside the skull or spinal canal, are caused by trauma. However, since patients with haemophilia can experience bleeding even weeks after a minor head injury, a history of head trauma may be hard to determine, particularly in children[17, 18].

Intestinal tract bleeding usually presents as obstruction due to intramural haemorrhage, but haematemesis and melaena also occasionally occur and should be routinely investigated, as they may be due to peptic ulcer or malignancy[16].

There is a wide spectrum of esophageal and gastrointestinal (GI) bleeding. A review of 41 episodes of gastrointestinal bleeding in one institution over 10 years implicated duodenal ulcer (22%) and gastritis (14%) as the most common source. In 22%, no source was identified. Mallory-Weiss Syndrome has also been cited as a cause for upper GI bleeding in haemophilia patients[20].

Surgery and open trauma invariably lead to dangerous haemorrhage in the untreated individual with haemophilia. There may be persistence of haemorrhage often after an initial short lived period of haemostasis. The incidence of bleeding in different sites is given in the tables 1 and 2[14].

Table 1: Incidence of different sites of bleeding in percentages

Site of bleeding Incidence in percentage

Haemarthroses 70%-80% Muscle/soft tissue 10%-20% Other major bleeds 5%-10% Central nervous system (CNS) bleeds < 5%

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Table 2: Incidence of bleeding in different joints

Joint Incidence of bleeding in %

Knee 45% Elbow 30% Ankle 15%

Shoulder 3% Wrist 3% Hip 2%

Other 2%

5.1.4.2 Laboratory findings Evaluation of an individual with a suspected bleeding disorder includes: platelet count and platelet function analysis (PFA closure times) or bleeding time, activated partial thromboplastin time (APTT), and prothrombin time (PT). Thrombin time and/or plasma concentration of fibrinogen can be useful for rare disorders[7, 8].

Screening tests show a long activated partial thromboplastin time (APTT), normal prothrombin time (PT), thrombin clotting time (TCT) and bleeding time, and a normal platelet count. Specific assays show factors VIII and IX clotting activity below 0.05 U/mL, with all other factors normal[21].

The normal level of factors VIII and IX is 50-150% and is measured by a clotting assay[7, 8]. In haemophilia the propensity to bleeding is related to the plasma factor VIII level. The classification of severity of haemophilia is set out in the Table 3[22]:

Table 3: Classification of severity of haemophilia

Severity Clotting factor level % activity (IU/ml) Bleeding episodes

Severe 1% (< 0.01) Spontaneous bleeding, predominantly in joints and muscles

Moderate 1%-5% (0.01-0.05) Occasional spontaneous bleeding. Severe bleeding with trauma, surgery

Mild 5%-40% (0.05-0.40) Severe bleeding with major trauma

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5.1.5 Treatment The major precept of haemophilia care consists of adequate replacement of the deficient coagulation factor protein so as to prevent or reverse acute bleeding episodes. This is most effectively and efficiently accomplished by the administration of clotting factor concentrates, which contain an abundance of the specific deficient coagulation factor [23].

5.1.5.1 Clotting factor concentrates Modern management of haemophilia began in the 1960’s when the first FVIII plasma concentrates became available. This first generation of FVIII enabled a much more effective treatment than simple plasma. The life expectancy and quality of life saw unprecedented improvement[24].The effect of replacement therapy has significantly improved the morbidity and mortality of people with haemophilia[25].

The introduction of coagulation factor replacement therapy over the past half century has greatly contributed to the improvement in care of people with haemophilia [26].Following the sequencing of the FVIII gene in 1984, the various mutations were identified (meaning that the severity of haemophilia and probability of the occurrence of inhibitors could be predicted) and the first recombinant concentrates were developed. The first generation of these rFVIII was licensed in 1993. Production of rFVIII using genetic engineering in theory eliminates the risk of infection by a human virus[13, 24]. Hamster cells are transfected with human clotting factor genes by recombinant DNA technology. Factor VIII produced by recombinant DNA techniques is available, safe, and effective[16].

5.1.5.2 DDAVP Desmopressin (1-deamino-8-D-arginine vasopressin, also known as DDAVP) is a synthetic analogue of antidiuretic hormone (ADH). The compound boosts the plasma levels of FVIII and vWF after administration [22]. It can be used to treat mild haemophilia. This synthetic analogue of vasopressin retains the antidiuretic action of the natural hormone and also stimulates the release of tissue plasminogen activator. In practice, these effects can be used to elevate the plasma factor VIII level two- to fourfold above the baseline, presumably by its release from storage site(s). DDAVP is contraindicated in elderly patients and those with vascular disease, because arterial thrombosis is a theoretical risk and has been reported following DDAVP in these circumstances[27].

5.1.5.3 Gene therapy Haemophilia continues to represent a leading candidate condition for the successful application of gene therapy[28].The ultimate goal of gene therapy is the replacement of a defective gene sequence with a corrected version to eliminate disease for the lifetime of the patient[29]. Although new paths to treatment are available, the path to a cure still has barriers that must be overcome. Whether some of these approaches might be applicable to human patients with inhibitory antibodies is not yet known, and additional preclinical studies are still needed [30].

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5.1.5.4 Comprehensive Care Concept Comprehensive haemophilia care has been defined as the continuing supervision of all medical and psychosocial factors affecting the person with haemophilia [31]. Comprehensive care is vital for patients with haemophilia to prevent early death and free patients from the complications that inhibit living normal lives. Experience has shown that once introduced in a country, there is a progressive restoration of normal healthy lives to the haemophilia community[5].

Services offered by haemophilia treatment centres (HTCs) adopting the comprehensive care model include establishing prophylaxis and other treatment protocols, development of psychosocial, education and research programme, maintenance of a patient registry, genetic and reference diagnostic services, orchestration and management of a wide variety of multidisciplinary interventions. Most centres practising this model of care are based in developed countries and can meet costs for plentiful treatment products through government or insurance-company funding. Not all the programmes are dependent on the level of product supply, however, many have been supported in countries with emerging economies as part of national healthcare systems, particularly in relation to blood management[31].

As the management of haemophilia is complex, it is essential that those with the disorder should have ready 24 hours access to a range of services provided by a multidisciplinary team of specialists [32]. Haemophilia is a relatively rare but complex disorder in terms of diagnosis and management. Optimal management of these patients, especially those with severe forms of the disease, requires more than the treatment and prevention of acute bleeding. Keys to improvement of health and quality of life include[33]:

•Prevention of bleeding•Long-term management of joint and muscle damage and other sequelae of bleeding•Management of complications from treatment including inhibitor development andviral infection(s) transmitted through blood products requiring long-term management.

These management goals are best met by a team of healthcare professionals providing comprehensive care. Haemophilia patients should ideally be managed in a comprehensive care centre staffed by the following core team members [31]:

• Haematologist(s);• Nurse coordinator;• Physiotherapist; and• Social worker.

These staff members should have expertise and experience in treating bleeding disorders. The core team members should have access to the following support resources[22]: • A coagulation laboratory capable of clotting factor assays and inhibitor detection;

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• Appropriate clotting factor concentrates, either plasma derived or recombinant;• If clotting factor concentrates are not available, a blood bank with expertise inpreparing fresh frozen plasma (FFP) and cryoprecipitate.

Specialists should be available as consultants, as needed, and should include, among others, the followings[33]. • Orthopedic surgeon;• Physiatrist/rheumatologist;• Occupational therapist;• Dentist;• Geneticist;• Hepatologist;• Infectious disease specialist; and• Immunologist.In centres where there are many patients with chronic musculoskeletal problems from frequent bleeding, an orthopaedic surgeon should be a core team member.

5.1.6 Prophylaxis Prophylaxis is defined as treatment by intravenous injection of factor concentrates in anticipation of and in order to prevent bleeding[34].It is recommended as preventive therapy for young boys with severe haemophilia in countries where safe factor concentrates are available[35].Prophylaxis can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A[36].To prevent hemophilic arthropathy, prophylactic treatment of children with severe haemophilia should be started before joint damage has occurred[37].

Many studies demonstrate the advantage of continuous FVIII prophylaxis over on-demand treatment in haemophilia A patients. Continuous prophylaxis reduces the number of bleeding episodes significantly. However, it cannot prevent bleeds completely and requires an almost 4-fold higher consumption of FVIII[38].

Prophylactic factor replacement therapy prevents the occurrence of joint bleeds and reduces the overall risk of disability associated with joint bleeds in haemophilia patients [39]. While primary prophylaxis(i.e. regular continuous long-term infusion of factor concentrates started before the age of two years and/or after no more than one joint bleed) is nowadays considered the gold standard for preserving joint function in patients with severe haemophilia, the benefits of secondary prophylaxis (i.e. all the long term regular treatments not fulfilling the criteria of primary prophylaxis) are still controversial[40].

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5.1.7 Complications of Haemophilia

5.1.7.1 Complications of therapy

5.1.7.1.1 Immunological reactions The immune response to factor VIII and factor IX, and the development of inhibitory antibodies is a complex multi-factorial process involving a variety of immune regulatory genes and cells, several of which have the potential to determine risk[41]. The development of inhibitors has been characterized as the most serious remaining complication of clotting factor treatment in persons with severe hemophilia. The characteristics of the mutation responsible for the disease is the strongest predictor of the risk of inhibitor development so far identified, but other genetic and environmental factors clearly are also involved[42].

Recent evidence suggests that alongside the strong genetic contribution to inhibitor formation, there are a number of non-genetic factors which promote formation of inhibitors [43]. Based on studies from around the world, it is estimated that the incidence of antibody development in persons with severe or moderately severe hemophilia A is between 20% and 33%. Among persons with haemophilia B, inhibitors are much less frequent, affecting only 1-6%[44].

Factors that appear to affect inhibitor development include the severity of haemophilia, age, genetics, and, possibly, the type of replacement therapy administered. Recent studies raise the concern that recombinant factor therapies may be associated with more rapid development and higher levels of inhibitors in previously untreated patients [33].

Management of patients with inhibitors involves control of acute bleeding episodes and, over the long term, induction of immune tolerance for the coagulation replacement therapy. Many with low or moderate levels of inhibitors may be treated simply by administering higher doses of dotting factor. Other therapies appropriate for those with high levels of inhibitors include porcine factor VIII and factor VIII bypassing agents, such as recombinant factor VIIa. Long-term immune tolerance has been achieved through the high-dose Bonn regimen and immunosuppressive regimens such as the Malmö method. Although management of inhibitor patients has improved, it still represents a major challenge [45].

Once replacement therapy is ineffective, acute management of bleeding requires agents that bypass factor VIII activity. Long-term management consists of eradicating the inhibitor through immune tolerance. Despite success in the treatment of acute bleeding and inhibitor eradication, there remains an inability to predict or prevent inhibitor formation. Ideally, prediction and ultimately prevention will come with an improved understanding of how patient specific and treatment-related factors work together to influence anti–factor VIII antibody production[46].

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5.1.7.2 Infectious Complications 5.1.7.2.1 Hepatitis Almost all multitransfused haemophilia patients treated before 1985 were infected with one or more agents of viral hepatitis. Although many infected patients did not suffer acute symptoms, at least 50 percent developed chronic persistent or chronic active hepatitis that led to cirrhosis[47]. The antigen-positive adult patients frequently have a superimposed infection with the delta agent, leading to severe active hepatitis and cirrhosis and an increased risk of hepatocellular carcinoma. Therapy with recombinant interferon alpha and ribavirin can reduce viral load and improve survival of affected patients[48]. A considerable number of these patients were also infected with human immunodeficiency virus (HIV)[49].

5.1.7.2.2 Human Immunodeficiency Virus (HIV) Many individuals who received blood products from 1979 to 1985 contracted HIV. Approximately half of these individuals died of AIDS prior to the advent of effective HIV therapy[8]. Most HIV infection in the haemophilic population occurred before the virus was discovered and therefore before individual donor testing was introduced [50, 51]. Following the identification in 1984 of HIV as the causative agent of AIDS, investigators discovered that heat treatment (60°C for more than two hours) of concentrated clotting factors inactivated HIV. This, with the development of serologic methods to screen blood for HIV and the self-deferral of high-risk blood donors, minimized further risk of infection in persons with haemophilia[52].

5.1.7.2.3 Prions Prions are infectious particles consisting of proteinaceous material devoid of a nucleic acid genome. Creutzfeldt-Jakob disease (CJD) is a member of a group of diseases known as Transmissible Spongiform Encephalopathies (TSEs) or prion diseases[53]. These are rare, fatal disorders that result in the progressive destruction of the nervous system. The potential for transmission of CJD through contaminated blood and blood products is of particular concern for the bleeding disorders community. Some studies support the idea that transmission of CJD by blood transfusions or blood products is very rare if it exists. However, because of the short incubation times seen in the studies and the very small number of cases, no one can definitely say that transmission is nonexistent[54].

5.1.7.3 Musculoskeletal complications

5.1.7.3.1 Muscle Haematomas Haemorrhages in muscle or soft tissue are particularly dangerous when they occur in closed compartments, such as the volar aspect of the wrist and forearm, the deep palmar compartments of the hand, or the anterior or posterior tibial compartments. Such nerve compression due to a closed space hemorrhage, known as “compartment syndrome,” can compromise limb function [55].

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5.1.7.3.2 Chronic haemophilic arthropathy The most common complication of haemophilia is crippling joint disease. The degeneration of a normal joint after recurrent bleeds is a result of a number of mechanisms which finally interact to produce severe distortion[56]. This can develop any time from the second decade of life, sometimes earlier, depending on the severity of bleeding and its treatment. With advancing cartilage loss, a progressive arthritis condition develops along with secondary soft tissue contractures, muscle atrophy, and angular deformities. The goal of treatment is to improve joint function and relieve pain. Supervised physiotherapy is a very important part of management at this stage. Factor replacement is necessary if recurrent bleeding occurs during physiotherapy. Pain should be controlled with appropriate analgesics. If these conservative measures fail to provide satisfactory relief of pain and improved function, surgical intervention may be considered[14].

Between the second and fourth decades, many haemophiliac patients develop severe articular destruction. At this stage possible treatments include joint debridement, arthrodesis and arthroplasty[57].

Total joint replacement has been successfully performed in people with haemophilia for over 30 years. By far the greatest numbers have been total knee replacements. The benefits of pain relief and improved function provided by total joint replacement make this procedure the most successful orthopedic operation for managing chronic hemophilic arthropathy[58].

5.1.7.3.3 Chronic synovitis The origin of haemophilic synovitis is clearly related to chronic accumulation of blood within a joint [59]. With repeated bleeding in a joint, the synovium becomes chronically inflamed and eventually hypertrophies, causing the joint to appear grossly swollen. This swelling is usually not tense, nor is it particularly painful. Diagnosis made by performing a detailed physical examination of the joint. The presence of synovial hypertrophy may be confirmed by ultrasonography and MRI. Plain radiographs and particularly MRI will assist in defining the extent of articular changes. The goal of treatment is to control the synovitis and maintain good joint function[14]. It has long been recognized that the emergence of chronic haemophilic haemarthroses is incited by a hypertrophic and highly vascular synovium and that removal of this synovium is the key to prevention of further joint damage. Removal of the synovium can be accomplished through surgical and non-surgical procedures[60].

5.1.7.3.4 Pseudotumour formation Pseudotumors are blood cysts that occur in soft tissues or bone. They are rare but dangerous complications of haemophilia. Most pseudotumors are not associated with pain unless rapid growth or nerve compression occurs. They usually contain either serosanguineous fluid or a viscous brownish material surrounded by a fibrous membrane. Computed Tomography (CT) scan or Magnetic Resonance Imaging (MRI) is useful for diagnosis. Needle biopsies of pseudotumors should be avoided because

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of the risk of infection and haemorrhage. Surgical management is the most effective treatment for pseudotumor, although more conservative therapies cannot be overlooked in selected cases [61, 62]. While pseudotumors in patients with haemophilia are in themselves not haemophilic emergencies, an acute rupture of a large pseudotumour in the pelvis or thigh may lead to acute hypotension from blood loss. When such an event occurs, an immediate correction of the FVIII or FIX level is indicated, while keeping in mind that the presence of chronic clots with fibrinolysis in the pseudotumour may also predispose to further haemorrhage[55].

5.1.7.3.5 Fracture Fractures are not uncommon in the person with haemophilia and occur most commonly around the knee and hip. The person with haemophilia is at risk for fracturing around joints that have significant loss of motion and in bones that are osteoporotic. Fractures managed with closed reduction and casts require clotting factor replacement therapy for 3-4 days, until swelling subsides[16].

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5.2 Haemophilia in Arabic countries

5.2.1 Health care in Arabic region Health care in Arabic countries is among the lowest levels worldwide. Although there are variations from country to country, in general the indicators of health care are low compared with western developed world. Many of these countries have now clear strategies towards an improved health care, but the expenditure on health is still low [63, 64].

The health care financing in Arabic countries is provided mainly from government revenues. The budgetary provision for the Ministries of Health has continued to increase (for example in Saudi Arabia from 2.8% of the national budget in 1970 to 5% in 2009). The remaining health services financing is derived from private sources (e.g. personal out-of pocket payments) and from occupational health insurance premiums mainly subscribed to by large private company employees[64]. Tables 4 and 5 shows the health expenditure and health indicators in Arabic countries.

Table 4: Health expenditure among Arabic countries1

Nr. Country GNI per capita in $

Total expenditure on health per

capita $ Total expenditure on health as % of

GDP 1. Jordan 5,720 499 9.3 2. Lebanon 11,750 1,054 8.1 3. Sudan 1,920 161 7.3 4. Djibouti 2,320 162 7.0 5. Tunisia 7,460 524 6.2 6. Algeria 7,890 544 5.8 7. Yemen 2,220 142 5.6 8. Morocco 4,190 251 5.5 9. Saudi Arabia 24,500 1,150 5.0

10. Egypt 5,470 282 5.0 11. Bahrain 33,430 1,557 4.5 12. Libia 16,270 709 3.9 13. Iraq n.a 167 3.9 14. Kuwait 53,480 1,498 3.3 15. Oman 22,170 787 3.0 16. Syria 4,490 138 2.9 17. Emirates 45,660 1,756 2.8 18. Somalia n.a 18 2.6 19. Mauritania 1,990 47 2.5 20. Qatar n.a 2,090 2.5

1 Source: World Health Organization, Countries profiles, 2009 22

Table 5: Health status indicators in Arabic countries2

Nr. Country Life

expectancy at birth m/f

Healthy life expectancy at

birth m/f

Probability of dying under 5 years per 1000 population

1. Emirates 77/79 64/64 7 2. Qatar 78/79 67/64 9 3. Bahrain 73/76 64/64 12 4. Oman 72/77 63/65 12 5. Lebanon 71/77 59/62 12 6. Kuwait 78/79 67/67 13 7. Syria 71/76 60/63 16 8. Libia 70/75 62/65 19 9. Tunisia 73/77 61/64 21 10. Saudi Arabia 69/75 60/63 21 11. Egypt 69/73 58/60 21 12. Jordan 69/74 60/62 25 13. Algeria 71/74 60/62 32 14. Morocco 71/75 59/61 38 15. Iraq 62/70 49/51 44 16. Yemen 63/66 48/51 66 17. Djibouti 58/62 43/43 94 18. Sudan 59/59 47/50 108 19. Mauritania 57/60 43/46 117 20. Somalia 54/56 36/38 145

5.2.2 Haemophilia care in Arabic world Haemophilia care in Arabic world shows variations from country to country. It varies from a good available care with presence of specialized haemophilia centers (e.g. Egypt, Jordan) to absence of care at all (e.g. Yemen, Somalia).

In the Global Survey of WFH in 2009, 9702 cases of haemophilia were reported from 13 Arabic countries [3, 9]. Of 22 countries of the Arab League, only 13 have at least one haemophilic center. Countries such Egypt, Algeria, Tunisia, Jordan and Syria have good organized programs and more than one haemophilia center. Other countries provide a relatively weak care compared to their financial resources; for example Saudi Arabia, with a population of about 24 million, and 326 reported cases of haemophilia has only one specialized care center for haemophiliacs[3].

Factor use also varies from country to country, according to economical level. High income countries consume large quantities; for example Saudi Arabia reported the highest use of factor concentrates in the region, about 191 736 IU per person with haemophilia A (PWHA)[25].

2Source: World Health Organization, Countries profiles, 2009 23

In other countries such as Yemen, Somalia, Djibouti, Mauritania, there is no specialized center and only little or no care for haemophiliacs is available. The major problems with regard to haemophilia care in those countries are[6]:

• Lack of facilities for a proper laboratory diagnosis;• Inadequate supply of safe factor concentrates.

The majority of population in such Arabic countries lives in rural area, under poor health care and where educational status is at the lowest levels with high illiteracy rate. Awareness and knowledge about the nature of the disease among patients and their families is low. Factor concentrates are available only in central hospitals, usually in the capital cities. Many haemophiliacs in villages have no access to factor concentrates and probably die from life threatening manifestations of the disease such as intracranial bleeding, before they reach the central clinics for a specialized treatment.

Table 6: Some indicators of haemophilia care among some Arabic countries3

Nr. Country Population in thousands

Estimated cases of

haemophilia4

Reported cases of

haemophilia

Number of Haemophilia

centers 1 Egypt 80,471 5,320 5,307 10 2 Algeria 34,178 2,260 1,291 10 3 Iraq 28.506 1,888 841 1 4 Sudan 41,087 2,500 618 1 5 Saudi Arabia 29,207 1,941 326 1 6 Syria 22,198 1,290 300 2 7 Tunisia 10.215 665 250 4 8 Jordan 6,342 412 248 3 9 Lebanon 4.055 266 165 1 10 Palestine 4,013 266 131 6 11 Qatar 833 56 112 2 12 Oman 3,418 226 93 2 13 Bahrain 739 50 20 1

3Source: World Federation of Haemophilia, Global survey report, 2009 4 These values were estimated according to prevalence rates used by WFH: Hemophilia A and B: 133 per million male population

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5.3 Haemophilia in Yemen

5.3.1 Introduction to Yemen

5.3.1.1 Geography and demography

Figure 1: Political Map of Republic of Yemen5

Republic of Yemen is located in Southwest Asia at the southern tip of the Arabian Peninsula between Oman and Saudi Arabia. It is situated at the entrance to the Bab-el-Mandeb Strait, which links the Red Sea to the Indian Ocean (via the Gulf of Aden) and is one of the most active and strategic shipping lanes in the world. Yemen has an area of 555,000 square kilometers, including the islands of Perim at the southern end of the Red Sea and Socotra at the entrance to the Gulf of Aden. Yemen’s land boundaries total 1,746 kilometers. Yemen borders Saudi Arabia to the north and Oman to the northeast[65].

According to the latest census in 2008, the Republic of Yemen had a population of 22.879.805 persons[66]. Yemen’s population has more than doubled since 1975 and has grown approximately 35 percent since the 1994 census, making Yemen the second most populous country on the Arabian Peninsula[64].

Population pyramid is with a wide base and about half of the population is under 15 years old adding to the burden on the health sector for their special diseases management and protective programs. Population growth rate, at 3.02 percent per year is among the highest in the world, family planning activities are minimal, and the use of modern contraceptives is particularly low at 13 percent[64].The situation is compounded by the wide regional disparities and the significant differences between urban and rural conditions.

The main demographic indicators are given in Table 7 and Figure 2.

5 World Fact Book, Middle East, Yemen Profile, 2010 25

Table 7: Demographic indicators on Yemen6

The indicator Values Year of estimation

Total population in thousands 22,198 2008

Males population in thousands 11,826 2008

Females population in thousands 10,372 2008

% Urban population out of total population

29 2008

Crude birth rate per 1000 population

39.7 2006

Crude death rate per 1000 population

9.0 2006

% Population growth rate 3.0 2007

% Population below 15 years 45.0 2007

% Population 65 years and over 3.5 2007

Total fertility rate (R) per woman 6.1 2006

Figure 2: Composition of Yemeni population by age groups7

6 Yemeni Ministry of Public Health and Population, Annual Report, 2009 7 WHO, Eastern Mediterranean Regional Office, Yemen profile, September 2009

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Figure 3: Life expectancy at birth8

Yemen’s population is predominantly Arab, but it also includes Afro-Arabs and South Asians. Arabic is the official language. English is also used in official and business circles. In the Mahra area (the extreme east), several non-Arabic languages (including Mehri) are spoken. Virtually all citizens of Yemen are Muslims, either belonging to the Zaydi order of Shi'a Islam or to the Shafa'i order of Sunni Islam. There are also Jews, Christians and Hindus.

5.3.1.2 Socio-economic status Yemen is one of the poorest countries in the Arab world and its economic fortunes depend mostly on oil. Most people are employed in agriculture and herding, services, construction, industry, and commerce account for less than one-fourth of the labor force. Unemployment rate is 15% and population below poverty line 34,8%. GDP is $26.6 billion, GDP - real growth rate is 3.9%, GNI - per capita is $1060 and labor force is 5.98 million[67].

5.3.1.3 Education Education indicators have improved during the last two decades but are still very low. The adult literacy rate is only 53 percent, and the gross enrollment ratio for basic education is 73 percent. Quality is widely acknowledged to be poor. The gender gap is among the widest in the world, with only 56 percent of primary school-aged girls in school, and much less freedom of female social and economic opportunity[64].

Some education indicators are given in Table 8.

8 WHO, EMRO, Yemen profile, September 2009 27

Table 8: Education indicators among Yemeni population9

Indicators Values in %

Adult literacy rate 15+ years, total 53

Adult literacy rate 15+ years, males 73

Adult literacy rate 15+ years, females 31

Gross primary school enrolment ratio - total 65

Gross primary school enrolment ratio - male 73

Gross primary school enrolment ratio - female

56

Gross secondary school enrolment ratio - total

50

Gross secondary school enrolment ratio - males

69

Gross secondary school enrolment ratio - females

31

5.3.1.3 Health care system The Yemen Health Care system represents about 95% of the total health care and services provided to the citizen with government finance to its prevention, medical and rehabilitation activities. Its structure is based on the health centers and units at the first touchline[66].

5.3.1.3.1 Public health care The health care system in Yemen consists of a large public sector with a sizable private sector. Public health care is organized in three levels: Primary Health Care (PHC) supported by secondary and tertiary referral care. PHC focuses on preventive health programs (immunization, Mother and Child Health (MCH) and family planning, health education, etc.) and provides first level curative care. It starts at the village level where PHC units are run by paramedical staff; the units are backed up by PHC centers, most of which are managed by one physician and have laboratory and X-ray facilities. Patients who cannot be properly managed at the PHC level are referred to rural, district or governorate hospitals (secondary care) for further diagnostic and curative treatment[66]. Some of these hospitals also provide support for national or regional immunization and disease control programs. Finally, tertiary hospitals provide specialized care and serve as teaching hospitals for the medical faculties of the country’s universities[64].

Tables 9, 10, 11 and 12 show some health indicators in Yemen.

9 WHO, EMRO, Yemen profile, September 2009 28

Table 9: Health expenditure indicators of Yemen10

Indicator Value Year

GDP per capita US$ exchange rate 1,060 2008

Total expenditure on health (per capita) US$ exchange rate

41 2006

Government expenditure on health (per capita) US$ exchange rate

21 2006

Total expenditure on health of % of GDP 4.5 2006

General government expenditure on health as % of total health expenditure

50.1 2006

Out-of-pocket expenditure as % of total health expenditure

47.5 2006

General government expenditure on health as % of total government expenditure

5.5 2006

Ministry of health budget as % of government budget

4.0 2006

Table 10: Public Health facilities in Yemen11

Facilities No

Referral Hospitals 2

General Hospitals 53

District Hospital 182

Health Center 793

Health Units 2774

Total Number of Health Facilities 3852

Referral Hospitals Beds 1207

General Hospitals Beds 8924

District Hospitals Beds 4669

Total Numbers of Beds 15184

10Source: WHO, Countries profiles, Yemen, 2008 11Source: Yemeni Ministry of Public Health and Population, 2009

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Table 11: Public Health Manpower12

Categories No

Physicians 6338

Dentist 535

Pharmacist 2336

Nurses 12227

Medical Assistants 2455

Morshed/ Morshedah13 2801

Technical Assistants 5729

Others 11182

Total 46331

Table 12: Health facilities per 10000 of population Items No

Hospitals 0.1

Beds 7

Physician 3

Dentist 0.2

Pharmacist 1

Nurses 7.3

Paramedical 10.2

Health Centers &Units 2

12 Source: Yemeni Ministry of Public Health and Population, 2009 13Health Advisor

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5.3.1.3.2 Private Health Care System (Modern, for-profit) The role of the private sector increasingly grows. It concentrated in the capital city and main cities of the governorates. The size of this sector indicates the availability of 1336 doctors’ clinic, 615 foreign doctors and 309 foreign technicians[66].There is evidence of an expanding role for the private for –profit health sector in the delivery of health services. Although the exact number and scope of their activities are not yet known, it is likely that the coordination of investment and activities between the public and the private sectors will become an important issue in the coming years[64]. Table 13 gives some information about private health facilities in Yemen.

Table 13: Private Health facilities14

Facilities No

Hospitals 167

Polyclinic 321

Health centers 420

Physicians clinic 1336

Spec. clinics 838

Dental clinic 654

Dental Lab 155

Laboratory 1189

Radiology Clinic 224

PHC 1355

Midwifery 69

Pharmacy 2681

Drug Stores 2123

These services are provided by the Non-governmental Organizations (NGO) local or international, religious or social. There are two local NGOs having wide health activities all over the country the first is the Yemen's Charity Society, which was launched and licensed in 1990. It had multiple agreements with the Ministry of Health, Social Fund for Development, international organizations, World Bank, and international NGOs for financing the health projects[64]. Their health facilities

14 Source: Yemeni Ministry of Public Health and Population, 2009 31

cover13 out of 20 governorates and they have 11,500 employees serving population of 786,959. They have 5 hospitals (2 are specialized), 11 health centers, 3 dispensaries, and 1 health unit. All these facilities are equipped with the latest technology. They also have outreach activities and school health provision. The second is the Society of Family Care, which provides all the reproductive health services and mainly works in Sana’a[66].

5.3.1.3.3 Traditional Traditional medicine still plays an important role in Yemen. In many rural areas, it is the only medical assistance available to people, but it also competes with modern public and private health care which is either more expensive or regarded with suspicion. Medical practices are rooted in the Greco-Arabic tradition and have physical as well a spiritual dimension. Some of the more common procedures are cupping to draw off blood, cautery, bone setting and minor surgical techniques. In addition, local plant and animal products, some minerals and changes in dietary habits are used to treat ailments. Local birth attendants assist with deliveries and provide post-natal care. There are many aspects of traditional health care which are beneficial to individuals and the community, and which could complement modern medical practice. Traditional cures are often effective although they fail with most of the endemic diseases.

5.3.1.3.4 Public /private interactions There is a private sector department at the MOPH with its policy and system but in reality it is only in papers and needs to be activated. There is a little interaction between the MOPH and the local NGO-s especially the Islah Social Charity Society, which implement some health projects with the MOPH. The interaction was based on competition with wide lack of coordination to improve the coverage and accessibility of health care services. The services were of low standards and there was poor management[68].

5.3.1.3.5 Health Insurance Currently the MOPH&P provide health insurance coverage only for the government employee. The private companies and organizations cover also their employees. The rest of population has no health insurance. The health insurance policies in Yemen are offered by private or nonprofit seeking organizations. At present, there are very few insurance companies in Yemen that offer insurance policies to both public and private organizations[66].

5.3.2 Epidemiology of Haemophilia in Yemen There are no official data about the prevalence of haemophilia in Yemen as there is no organized care strategy for this disease. The cases are not reported and even the major hospitals or the Ministry of Health have no registry or statistics regarding haemophilia patients. However, referred to the standard incidence used by WHO and WFH, Yemeni haematologists estimate that about 1460 people in Yemen are affected by haemophilia[69].

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Something that could be considered as specific for Yemen and Arabic countries in general, is the fact of consanguinity and marriage between the members of same large family15. This factor may probably increase the prevalence of this disease in this Arabic country. A haemophilia study was made among a large family in a province of Yemen. The pedigree was composed of 76 members, including 33 females and 43 males. 27.2 % of the females were obligative carriers, each having at least one hemophilic son. 39.5 % of males were hemophilic, and among them 64.7 % died of hemophilia at age ranging from 20 days to 26 years, while the rest still live[70].

During my visit to the Branch of Blood Diseases at Thawra General Hospital in capital city, Sana’a, I found that during second half of year 2009, were treated 135 cases of haemophilia. The age of patients varied between 11 months and 29 years. Most of cases were considered as severe according to the clotting factor assay.

5.3.3 Ways of management, facilities, centres and clinics Republic of Yemen is the only country of Arabic peninsula without a specialized centre for haemophilia. Taking in consideration that Yemen is a poor developing country spending about 5,6 % of its GDP on the health care, the Ministry of Health concern is focused on the major health problems of the country, such as Infectious diseases16 and Malignancies. As a result only a small or no attention is paid to rare diseases such as haemophilia.

There are only two hospitals in the capital city, which offer treatment for Yemeni haemophiliacs. Thawra General Hospital and Republican Hospital are the two largest government hospitals in the country. In either of them, there is a branch of Haematology, at the Internal Medicine Department, dealing with haemophilia cases.

Many cases are diagnosed accidentally during routine investigations done before surgical interventions or after circumcision. Usually, the new cases are diagnosed by haematologists or internists at their private clinics and then they are referred to the centres mentioned above. After the confirmation of the diagnosis, the patients are either admitted as stationary or treated as day ambulatory cases with factor concentrates. No unified protocol is used by haematologist, and each of them follows certain recommendations and protocols following the international literature and guidelines. Patients with complications are treated in other departments according to their conditions [71].

Until year 2000 there was no factor concentrates available, and the cases were either treated with FFP or DDAVP or referred outside the country for a better treatment. After an absence for two years (2007-2009), factor concentrates are again available in adequate amount. They are supposed to be offered free of charge by Ministry of Health, which supply only the two hospitals mentioned above[69, 70].

15Marriage between cousins in Arabic countries is a common old tradition 16About 15000 people die annually from Malaria, which is endemic in many areas of Yemen

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As no specialized centre is available, there is no comprehensive care and no educational program about the nature of the disease and its prophylaxis. Absence of genetic counseling and in-existence of facilities for early and prenatal diagnosis, are among the factors that help in the increase of number of haemophiliac individuals in Yemeni community[70].

Another challenge for haemophiliacs in Yemen is the large distance they have to cross, from their hometowns and villages until they reach the capital city. Most of the population lives in rural areas where no facilities are available. With a difficult mountainous terrain and a bad infrastructure, many of them have to travel more than 10 hours with their own cars, until they arrive in Sana’a. Under such conditions some of hemophiliacs with severe forms of the disease and life threatening complications have little chances to survive.

Another treatment option is referring of cases outside the country. Some patients, who are capable to pay the high costs of such choice, choose other Arabic countries like Egypt or Jordan or even western countries, seeking for a better care. However, the poor majority of haemophiliacs do not have such a chance[69].

5.3.4 Costs and financial resources Haemophilia is a complex health problem rather than only a deficiency of a single clotting factor. The impact and consequences of this disease affect significantly the socio-economic status of the community. For a proper care of a haemophilic patient, thousands of dollars are needed every year.

In a country such Yemen, neither government nor the patient are able to pay for a proper management. The Yemeni Ministry of Health is supposed to provide factor concentrates free of charge for every haemophilic patient according to the need, but nothing more. In the absence of health insurance system, the patient should pay for every kind of intervention and management of subsequent complications. Even the services provided by government hospitals are not free.

In Yemen, as in many other countries, the health services are under a severe financial strain which cannot be resolved with the present budgetary allocations. The actually available funds for health care provision are insufficient and the burden of obtaining adequate quality care is left to the individual patient, often at high cost [71].

In 1994, a cost sharing strategy has been introduced. Its objective was to secure sufficient funds through revenues from fees and charges for services in order to improve maintenance of facilities and supply of drugs, as well as the motivation and performance of health personnel. Cost sharing in Yemen depends on two types of charges. The first is fee for service, or user fees, for curative services. In Yemen, it is expected that user fees will contribute approximately 10-15% to overall running costs in government facilities. The second type of charge will be for essential drugs. The government will import low cost, good quality, generic essential drugs, and recover

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100% of